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Investigating metformin and cocaine interactions in the brain at the level of pharmacokinetics, physiology, and proteomics

Award Number: R01DA066533
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Investigating metformin and cocaine interactions in the brain at the level of pharmacokinetics, physiology, and proteomics - PROJECT SUMMARY/ABSTRACT Stimulant involved overdose deaths in the United States, including cocaine, have been increasing since 2011. Despite the pressing need, there are still no FDA-approved pharmacotherapies for treatment of cocaine use disorder (CUD). Consequently, there remains a critical need to identify effective treatments for CUD. Our preclinical studies provide support for repurposing metformin (MET), a drug commonly prescribed for the treatment of type 2 diabetes, for treatment of CUD. We find that MET impairs the development of locomotor sensitization to cocaine, reduces cocaine conditioned place preference, and decreases cue-induced reinstatement of cocaine seeking following self-administration. MET works, in part, through activation of adenosine monophosphate activated protein kinase (AMPK), but our previous studies did not provide strong support for AMPK as the sole mediator of the effects of MET on cocaine-related behaviors. Therefore, the primary objective of this proposal is to interrogate the cellular and molecular mechanism responsible for the effects of MET on cocaine-related behaviors. This will position us to advance the translation of MET as a CUD therapy and facilitate further development of targeted, mechanistically informed therapies. Aim 1 will define the pharmacokinetics of MET in the brain and drug-drug interactions between MET and cocaine including an exploration of the role of organic cation transporter (OCT) proteins involved in MET uptake. We will quantity MET biodistribution in brain using liquid chromatography-mass spectrometry (LC-MS) and measure the distribution and relative abundance of OCTs with Western blot and immunohistochemistry. The necessity of OCT proteins for CNS uptake of MET and effects on cocaine-induced locomotor sensitization will be tested with a pharmacological inhibitor cimetidine. We anticipate cocaine will alter MET pharmacokinetics, and we predict OCT inhibition will occlude the inhibitory effect of MET on cocaine-induced locomotion. Aim 2 will test whether MET influences glutamate release or cocaine dysregulated glutamate homeostasis following self-administration. Glutamate uptake assays will measure the effects of MET on glutamate transporter function ex vivo. Fiber photometry with fluorescent glutamate biosensor (iGluSnFR3) will be performed to assess the effects of MET on glutamate release in vivo. We predict that MET will normalize cocaine-induced changes in glutamate signaling. Aim 3 will identify effects of MET on the proteome and phosphoproteome in the brain. Liquid chromatography- tandem mass spectrometry (LC-MS/MS) will be used to quantify protein changes associated with MET treatment in immortal cell lines or within brain tissue in the presence or absence of cocaine experience. We predict that by comparing the MET proteome between saline and cocaine treated conditions we will identify a unique set of proteins involved in mediating the effects of MET on cocaine-related behaviors. These results will provide important insights into the brain mechanisms of action of MET in support of translating this drug to the clinic.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $530,369 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Drug Use and Addiction Research Programs	000	1	8/28/2026	NEW	$530,369
														Subtotal = $530,369

Grand Total All Awards = $530,369

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Investigating metformin and cocaine interactions in the brain at the level of pharmacokinetics, physiology, and proteomics

Award Number: R01DA066533

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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